Spotlight on Research 2014

May 2014

International Team Identifies Biomarker for Scleroderma

A higher level of a small signaling molecule correlates with a more severe form of scleroderma, a chronic autoimmune disorder that involves the abnormal growth of connective tissue, according to a study funded in part by the NIHís National Institute of Arthritis and Musculoskeletal and Skin Diseases and published in The New England Journal of Medicine. The findings suggest that the molecule, CXCL4, could be used as a diagnostic marker for the disease and as a therapeutic target.

Scleroderma is an autoimmune disease characterized by damage to blood vessels and thickening and scarring of the skin. In some cases, internal organs can be damaged as well. The severity and symptoms of the disease vary widely among patients. Some people diagnosed with scleroderma develop fatal complications involving the lungs or the kidneys. Others are able to control the symptoms and have a normal life span.

While there is no cure for scleroderma, medicines such as those that lower blood pressure and block stomach acid can help control some of its symptoms. Treatments for more severe forms that affect internal organs carry significant risks. For example, the anti-cancer compound, cyclophosphamide, is used to treat scleroderma, but the drug is toxic and cannot be used indefinitely.

A biomarker that reflects disease severity would enable physicians to personalize therapies, treating some patients aggressively, while sparing others the side effects of some of the more potent medications. Such a marker could also help researchers test the effectiveness of novel treatments.

"Biomarkers would help us understand more quickly how patients are responding to new medications that are under development for this disease," said study author Robert Lafyatis, M.D., of the Boston University School of Medicine. "This would enable us to more rapidly identify new therapies in early clinical trials."

With this goal in mind, Dr. Lafyatis helped form an international network of scleroderma researchers. By collaborating, the scientists were able to capitalize on their diverse expertise and assemble sufficient numbers of patients to proceed with the study.

Little is known about what causes scleroderma, but evidence suggests it stems from immune system malfunction. The team chose to focus on immune cells called plasmacytoid dendritic cells (pDCs) because they previously had been implicated in autoimmune diseases such as rheumatoid arthritis and lupus. Studies had also suggested that pDCs were involved in scleroderma, but their precise role had not yet been defined. Dr. Lafyatis and his colleagues suspected that pDCs might be secreting a factor that brought about some of the diseaseís characteristics.

By taking a comprehensive approach and analyzing all proteins secreted by pDCs, the researchers noticed that one in particular stood out—CXCL4, a small signaling molecule involved in inflammation and wound repair. pDCs from people with scleroderma produced more CXCL4 than any other protein, and hundreds of times more than pDCs from healthy controls.

The researchers also noticed a more subtle trend—pDCs from people with severe forms of scleroderma secreted more CXCL4 than those with mild disease, suggesting that the molecule could be used to determine a patientís prognosis and treatment regimen.

To see if they could gain a better understanding of CXCL4ís role in scleroderma, the scientists next tested the effects of the molecule on laboratory-grown cells. When they treated human vascular endothelial cells, a type of cell that lines blood vessels, with CXCL4, the cells boosted their production of a molecule that narrows blood vessels. CXCL4 also reduced the level of another molecule, FLI1, which is involved in blood vessel formation.

Together, these findings suggested that CXCL4 could shrink the network of blood vessels in certain parts of the body, one of the vascular problems associated with scleroderma.

The researchers then examined the effect of CXCL4 in laboratory mice. When treated with CXCL4, the miceís skin developed signs of inflammation, a typical feature of scleroderma. But the inflammation did not progress to scarring, suggesting that CXCL4 is an important contributor to the skin problems associated with the disease, but is not the sole factor.

"We have identified a molecule that closely maps with the progression of scleroderma," said Dr. Lafyatis. "This is one of several biomarkers we have found that provides valuable information about disease severity and that will prove helpful in clinical trials, and eventually, patient treatment."

The mission of the NIAMS, a part of the U.S. Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.